Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2016; 22(16): 4120-4135
Published online Apr 28, 2016. doi: 10.3748/wjg.v22.i16.4120
Combined mesenchymal stem cell transplantation and interleukin-1 receptor antagonism after partial hepatectomy
Jian-Feng Sang, Xiao-Lei Shi, Bing Han, Xu Huang, Tao Huang, Hao-Zhen Ren, Yi-Tao Ding
Jian-Feng Sang, Xiao-Lei Shi, Bing Han, Xu Huang, Tao Huang, Hao-Zhen Ren, Yi-Tao Ding, Department of General Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
Author contributions: Sang JF and Shi XL contributed equally to this work; Sang JF and Shi XL designed the research; Sang JF, Han B, Huang T, Huang X, and Ren HZ performed the research; Ding YT provided new reagents/analytic tools; Sang JF and Han B analyzed the data and wrote the paper. All authors have read and approved the final manuscript.
Supported by The National Natural Science Foundation of China, No. 81300338; 863 National Science and Technology Plans, No. 2013aa020102; and Project Fund of Clinical Medical Center of Digestive Diseases in Jiangsu Province, No. bl2012001.
Institutional review board statement: The study was reviewed and approved by the Nanjing Drum Tower Hospital Institutional Review Board.
Institutional animal care and use committee statement: All animal procedures were approved by the Animal Care Ethics Committee of Nanjing Drum Tower Hospital, Nanjing, China.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Yi-Tao Ding, Professor, Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China. yitaoding@hotmail.com
Telephone: +86-25-83304616-66866 Fax: +86-25-83317016
Received: July 3, 2015
Peer-review started: July 6, 2015
First decision: August 26, 2015
Revised: September 24, 2015
Accepted: December 12, 2015
Article in press: December 14, 2015
Published online: April 28, 2016
Processing time: 290 Days and 10.9 Hours
Abstract

AIM: To study the therapeutic effects of mesenchymal stem cells (MSCs) and an interleukin-1 receptor antagonist (IL-1Ra) in acute liver failure.

METHODS: Chinese experimental miniature swine (15 ± 3 kg, 5-8 mo) were obtained from the Laboratory Animal Centre of the Affiliated Drum Tower Hospital of Nanjing University Medical School. Acute liver failure was induced via 85% hepatectomy, and animals were treated by MSC transplantation combined with IL-1Ra injection. Blood samples were collected for hepatic function analysis, and the living conditions and survival time were recorded. Liver injury was histologically analyzed. Hepatic cell regeneration and apoptosis were studied by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. The levels of protein kinase B and nuclear factor-κB expression were analyzed by Western blotting.

RESULTS: MSCs were infected with a lentivirus for expression of green fluorescent protein (GFP) for subsequent identification; 97.3% of the MSCs were positive for GFP as assessed by flow cytometry. Additional flow cytometric analysis of cell surface marker expression demonstrated that > 90% of GFP-expressing MSCs were also positive for CD29, CD44, and CD90, indicating that most of these cells expressed typical markers of MSCs, and the population of MSCs was almost pure. Transplantation of MSCs in combination with 2 mg/kg IL-1Ra therapy significantly improved survival time compared to the acute liver failure model group (35.3 ± 6.7 d vs 17.3 ± 5.5 d, P < 0.05). Combined therapy also promoted improvement in serum inflammatory cytokines and biochemical conditions. The observed hepatic histopathologic score was significantly lower in the group with combined therapy than in the model group (3.50 ± 0.87 vs 8.17 ± 1.26, P < 0.01). In addition, liver cell apoptosis in the combined therapy group was significantly inhibited (18.1 ± 2.1% vs 70.8 ± 3.7%, P < 0.01), and hepatic cell regeneration increased. A significant increase in protein kinase B expression and decrease in nuclear factor-κB expression were observed (P < 0.01), which supports their important roles in liver regeneration.

CONCLUSION: MSCs and IL-1Ra had a synergistic effect in liver regeneration via regulation of inflammation and apoptotic signaling.

Keywords: Mesenchymal stem cells, Interleukin-1 receptor antagonist, Stem cell transplantation, Acute liver failure, Hepatoectomy

Core tip: Combination therapy is superior to any method of mesenchymal stem cell (MSC) transplantation used alone. This study shows that combination therapy improved liver function, inhibited apoptosis, and prolonged the survival of swine with acute liver failure (ALF). Transplanted MSCs may participate in liver regeneration by promoting proliferation and inhibiting apoptosis during the initial stage of ALF following antagonism of interleukin-1 inflammatory signaling. Combination therapy with MSC transplantation and an interleukin-1 receptor antagonist, which enables restoration from ALF and liver reconstruction in swine, is a promising treatment option for ALF patients in the future.